Nonlinear analysis of the heartbeats in public patient ECGs using an automated PD2i algorithm for risk stratification of arrhythmic death

Heart rate variability (HRV) reflects both cardiac autonomic function and risk of arrhythmic death (AD). Reduced indices of HRV based on linear stochastic models are independent risk factors for AD in post-myocardial infarct cohorts. Indices based on nonlinear deterministic models have a significantly higher sensitivity and specificity for predicting AD in retrospective data. A need exists for nonlinear analytic software easily used by a medical technician. In the current study, an automated nonlinear algorithm, the time-dependent point correlation dimension (PD2i), was evaluated. The electrocardiogram (ECG) data were provided through an National Institutes of Health-sponsored internet archive (PhysioBank) and consisted of all 22 malignant arrhythmia ECG files (VF/VT) and 22 randomly selected arrhythmia files as the controls. The results were blindly calculated by automated software (Vicor 2.0, Vicor Technologies, Inc., Boca Raton, FL) and showed all analyzable VF/VT files had PD2i < 1.4 and all analyzable controls had PD2i > 1.4. Five VF/VT and six controls were excluded because surrogate testing showed the RR-intervals to contain noise, possibly resulting from the low digitization rate of the ECGs. The sensitivity was 100%, specificity 85%, relative risk > 100; p < 0.01, power > 90%. Thus, automated heartbeat analysis by the time-dependent nonlinear PD2i-algorithm can accurately stratify risk of AD in public data made available for competitive testing of algorithms

Risk stratification for arrhythmic death in an emergency department cohort: a new method of nonlinear PD2i analysis of the ECG

Heart rate variability (HRV) reflects both cardiac autonomic function and risk of sudden arrhythmic death (AD). Indices of HRV based on linear stochastic models are independent risk factors for AD in postmyocardial infarction (MI) cohorts. Indices based on nonlinear deterministic models have a higher sensitivity and specificity for predicting AD in retrospective data. A new nonlinear deterministic model, the automated Point Correlation Dimension (PD2i), was prospectively evaluated for prediction of AD. Patients were enrolled (N = 918) in 6 emergency departments (EDs) upon presentation with chest pain and being determined to be at risk of acute MI (AMI) >7%. Brief digital ECGs (>1000 heartbeats, ∼15 min) were recorded and automated PD2i results obtained. Out-of-hospital AD was determined by modified Hinkle-Thaler criteria. All-cause mortality at 1 year was 6.2%, with 3.5% being ADs. Of the AD fatalities, 34% were without previous history of MI or diagnosis of AMI. The PD2i prediction of AD had sensitivity = 96%, specificity = 85%, negative predictive value = 99%, and relative risk >24.2 (p ≤ 0.001). HRV analysis by the time-dependent nonlinear PD2i algorithm can accurately predict risk of AD in an ED cohort and may have both life-saving and resource-saving implications for individual risk assessment

Monoclonal antibodies to sweet taste proteins. I. Analysis of antigenic epitopes on thaumatin by competitive inhibition assays

Using a competitive inhibition binding immunoassay, we have examined some of the antigenic epitopes present on thaumatin, an intense sweet tasting protein from the African fruit katemfe. We have developed a library of monoclonal antibodies which react with different surface antigenic epitopes on thaumatin. Some of these monoclonal antibodies also cross-react with monellin, another unrelated sweet tasting protein. The competitive binding immunoassay examines the immunoreactivity of both solid-phase and liquid-phase monoclonal antibodies. At least six major antigenic epitopes on thaumatin were identified by our library of monoclonal antibodies. This type of competitive binding analysis may prove useful in the discovery of "sweet taste determinants" on plant proteins and in the development of tandem immunoassays for quantitation of sweet tasting proteins in plant extracts

PD2i traces from arrhythmia controls and malignant arrhythmia subjects for the first half of the data set

PD2i values are expressed in degrees of freedom (dimensions) and the heartbeats are those obtained in a 15- to 30-min ECG up to the end or point of VF/VT onset. Note the low-dimensional excursions of the PD2i in the VF/VT subjects. The horizontal a priori criterion lines are set at 1.4 degrees of freedom and completely separate the two groups of patients. The rejected PD2i points are due to noise produced by arrhythmias and movement artifacts, but %N remains high enough in these patients for valid analysis. Surrogate- and %N-rejected files (n = 11) are not shown as they were a priori rejected (5 VF/VT, 6 controls). These rejected files contained all subjects with atrial fibrillation and the highest arrhythmia rates (ie, greater than 10% arrhythmias in all beats).<p><b>Copyright information:</b></p><p>Taken from "Nonlinear analysis of the heartbeats in public patient ECGs using an automated PD2i algorithm for risk stratification of arrhythmic death"</p><p></p><p>Therapeutics and Clinical Risk Management 2008;4(2):549-557.</p><p>Published online Jan 2008</p><p>PMCID:PMC2504053.</p><p>© 2008 Skinner et al, publisher and licensee Dove Medical Press Ltd.</p

Local and transmitted conformational changes on complexation of an anti-sweetener Fab

Crystal structures of an Fab (NC6.8) from a murine IgG2b(κ) antibody and its complex with a sweet-tasting, N-, N'-, N''-trisubstituted guanidine compound (NC174) have been determined by X-ray analysis. Both crystal forms are produced by a microseeding technique in polyethylene glycol (PEG) 8000 but the habits and space groups are very different. The native protein crystallizes as plates in the monoclinic space group C2 and the complex crystallizes as prisms in the orthorhombic space group P222. The structures were solved by molecular replacement methods, with the Fab fragments from the 4-4-20, HyHel-5 and BV04-01 antibodies as starting models. On binding of the ligand, N-(p-cyanophenyl)-N'-(diphenylmethyl)-N''-(carboxymethyl)guanidine, the protein exhibits significant local conformational changes in the active site, particularly in the third complementarity-determining region (CDR3) of the heavy chain. The ligand enters the small crevice by end-on insertion with the cyanophenyl group in the lead and the diphenyl rings partially protruding from the entrance. No strict π-π stacking interactions are observed. However, tyrosine L32 (CDR1), tyrosine L96 (CDR3) and tryptophan H33 (CDR1) help immobilize the cyanophenyl ring and guanido group, and tyrosine H96 moves about 4.5 Å to lie between the rings of the diphenyl group. The positive charge on the guanido group is compensated by glutamic acid H50 (CDR2) while the negative charge on acetic acid is neutralized by arginine H56 (CDR2) and by hydrogen bonding with asparagine H58 (CDR2). Water molecules participate in the binding process by hydrogen bonding with the cyano and guanido groups. The mechanism of binding is a clear example of induced fit. Like hemoglobin, the NC6.8 Fab can be classified as an allosteric protein, since its overall structure is altered by the binding of a small ligand. In crystals of the native Fab the elbow bend angle is 184° while in crystals of the complex the elbow angle is 153°. There is also a reciprocal push-pull type of change where the heavy chain is flexed and the light chain is extended. The tail of the heavy chain, which would be connected to the Fc in an intact antibody, is displaced 19 Å relative to its position in the unliganded Fab. Within the limited series of sweetener-Fab complexes we have thus far examined, only the NC174 hapten has produced such results. Complexes of NC6.8 Fab with NC24 or NC90 (2-dimethyl-4-methylbicyclo [2.2.1] heptanyl or cyclooctanyl derivatives of guanidine) crystallize in the same space group as the native NC6.8 and have structures resembling the latter rather than the Fab liganded with NC174

PD2i Heart Rate Complexity Measure can Detect Cardiac Autonomic Neuropathy: an Alternative Test to Ewing Battery

Abstract This study evaluates the usefulness of a new heart rate variability (HRV

Risk stratification for arrhythmic death in an emergency department cohort: a new method of nonlinear PD2i analysis of the ECG.

Heart rate variability (HRV) reflects both cardiac autonomic function and risk of sudden arrhythmic death (AD). Indices of HRV based on linear stochastic models are independent risk factors for AD in postmyocardial infarction (MI) cohorts. Indices based on nonlinear deterministic models have a higher sensitivity and specificity for predicting AD in retrospective data. A new nonlinear deterministic model, the automated Point Correlation Dimension (PD2i), was prospectively evaluated for prediction of AD. Patients were enrolled (N = 918) in 6 emergency departments (EDs) upon presentation with chest pain and being determined to be at risk of acute MI (AMI) \u3e7%. Brief digital ECGs (\u3e1000 heartbeats, approximately 15 min) were recorded and automated PD2i results obtained. Out-of-hospital AD was determined by modified Hinkle-Thaler criteria. All-cause mortality at 1 year was 6.2%, with 3.5% being ADs. Of the AD fatalities, 34% were without previous history of MI or diagnosis of AMI. The PD2i prediction of AD had sensitivity = 96%, specificity = 85%, negative predictive value = 99%, and relative risk \u3e24.2 (p ≤ 0.001). HRV analysis by the time-dependent nonlinear PD2i algorithm can accurately predict risk of AD in an ED cohort and may have both life-saving and resource-saving implications for individual risk assessment